Neuroinflammatory Processes in Drug Addiction: Chapter Outline

20
Neuroinflammatory Processes in Drug

Addiction
LEON G. COLEMAN, JR., AND FULTON T. CREWS
CHAPTER OUTLINE
Innate Immune Signaling in the Brain
Immune Cells of the Brain
generation of reactive oxygen species (ROS) through increased
Pattern Recognition Receptors and Their Ligands inducible nitric oxide synthase (iNOS) and nicotinamide adenine
Immune Signaling Molecules as Neuromodulators dinucleotide phosphate (NADPH)-oxidase expression. The M2
Addiction as a Neuroimmune Disease state is associated with the release of canonical antiinflammatory
Neuroimmune Components of the Stages of Addiction
cytokines such as IL-10 and IL-4. Microglia also regulate physi-
ological processes in the healthy brain, such as synaptic pruning,
Neuroimmune Signaling in Alcoholism debris clearance, immune surveillance/defense, and neurogen-
The Role of Endogenous TLR Agonist DAMPs in the Pathology esis.96,97 Astrocytes are another important cell type in the neu-
of Addiction roimmune system.64 Astrocytes express immune receptors and
Neuroimmune Activation and the Progression to Addiction cytokines in response to immune activation.89 Astrocytes undergo
Neuroimmune Basis of Addiction—A Work in Progress an activation known as reactive gliosis to help limit tissue damage
in different contexts.141 Some suggest that astrocytes adopt proin-
Future Immune Therapies for Addiction
flammatory and antiinflammatory states, similar to microglia.87,111a
Toward Novel Addiction Treatment Strategies Based on Astrocytes are also involved in numerous physiological processes,
Immune Pharmacology such as maintenance of fluid homeostasis, metabolic support
of neurons, and modulation of synaptic transmission through
uptake of glutamate.98 Both alcohol and cocaine also cause astro-
cyte activation.2,142,178 It is important to note that both microglia
and astrocytes regulate synaptic plasticity. Thus their activation
Innate Immune Signaling in the Brain by drugs of abuse might result in synaptic changes and neuronal
firing. Of interest, neurons have also been proposed to play a role
Immune Cells of the Brain in innate immune responses through modulation of glia and the
Historically the brain has been considered an “immune privi- induction of cytokines.105,106 In addition, a variety of cytokine
leged” organ, meaning it is protected from immune activation that receptors, such as those for,97a suggesting that neurons respond
occurs in the periphery. Currently, this is largely considered true; to cytokines. Indeed, IL-1β, monocyte chemoattractant protein-1
however, the brain has its own immune defenses. The resident (MCP-1) and other immune-signaling molecules alter neuronal
immune defenses in the brain are known to be composed of innate firing and modulates γ-aminobutyric acid (GABA) transmis-
immune responses. This allows for recognition and elimination of sion.11,12,159 These studies indicate that in the brain, cytokines and
viral, bacterial, and fungal pathogens. Historically, immune func- other immune-signaling molecules modify synapses and neurocir-
tion in the brain has primarily been considered the role of glial— cuits similar to neurotransmitters.
microglia and astrocytes. Microglia are the resident macrophages
of the brain and derive from mesodermal tissue-specific mono-
cytes. Microglia transition from a resting state to various stages of Pattern Recognition Receptors and Their
activation in response to infections, stressors, and drugs of abuse Ligands
such as alcohol and cocaine.a Stages of microglial activation have
been traditionally classified as M1 (proinflammatory) and M2 The innate immune system functions to recognize foreign
(antiinflammatory). M1 activation is associated with the release pathogens for their elimination. These pathogenic elements are
of canonical proinflammatory cytokines such as tumor necrosis detected by pattern recognition receptors (PRRs). These recep-
factor α (TNFα), interleukin 1β (IL-1β), and IL-6, as well as tors recognize specific molecular signatures associated with bac-
teria and viruses, termed pathogen-associated molecular patterns
aReferences 20, 45, 76, 79, 142, 154, 167. (PAMPs). PRRs are promiscuous receptors that have also been
277
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278 PA RT I I I Visualizations and Workings of the Addicted Brain
TABLE 20.1 S
elected Toll-like Receptors (TLRs) implicated in Addiction and Neurological Diseases
TLR Foreign Immunogen Endogenous TLR Ligand Neuropsychiatric Disease
2 Bacterial di- and tri-acylated polypeptides37 α-Synuclein Alcoholism
Gram (+) lipoglyans24 Parkinson disease99
3 dsRNA Stathmin, dsRNA Alzheimer disease85
Multiple sclerosis36
4 Bacterial endotoxin HMGB1 Alcoholism50
Peptidoglycans HSPs 60, 70/72176 Cocaine abuse
Stroke, traumatic brain injury
Chronic pain
7 ssRNA109 Let-7, miR-21 Alcoholism45
Alzheimer disease110
Chronic pain136
HMGB1. High-mobility group box.

found to recognize endogenous molecules associated with cell activating NF-κB. Some suggest that neurons do,not118 while oth-
stress or trauma, known as damage-associated molecular patterns ers find that NF-κB activation in glutamatergic and cultured neu-
(DAMPs). This is considered “sterile” inflammation, when innate rons regulates plasticity, learning, and memory.93,106 Furthermore,
immune activation occurs without the presence of a foreign patho- activated NF-κB subunit colocalizes with dorsal horn spinal neurons10
gen. The release of DAMPs has been implicated in the pathologies and different neuronal cell lines exhibit NF-κB-dependent regula-
of numerous peripheral immunological diseases. DAMP release tion of μ-opioid receptor expression.31,185
also occurs in the brain, which is normally a sterile environment. A key feature of TLR signaling is the induction of proinflam-
PRRs play critical roles in addiction pathology.49 To date, five matory DAMP release. These DAMPs can subsequently further
classes of PRRs have been identified including: Toll-like recep- TLR activation by binding to their respective receptors. Because
tors (TLRs), C-type lectin receptors, nucleotide binding domain the brain is sterile, TLR activation in the brain in response to drugs
receptors (leucine-rich repeat containing or nucleotide-binding of abuse likely involves DAMP-mediated signaling. One such
oligomerization domain [NOD]-like receptors), RIG-I-like recep- DAMP that has been found to play a role in alcohol addiction in
tors, and absent in melanoma 2 (AIM2)-like receptors35. TLRs are particular is the protein high-mobility group box 1 (or HMGB1),
the most studied PRRs, and have been implicated in both cocaine a nuclear chromatin binding protein that can be released during
and alcohol addiction.8,130,143 To date, 10 TLRs have been identi- cellular stress, activation, or damage. Upon its release, HMGB1
fied in humans and 12 in mice.35 TLR ligands include a variety of acts as an immune mediator via TLR4 or RAGE receptors.88,127
molecules from bacterial endotoxin to mammalian high-mobility HMGB1 has been implicated in alcohol addiction pathology and
group box 1 (HMGB1) and heat shock proteins176 (Table 20.1). might be involved in other drugs of abuse (detailed further later
TLRs are characterized by an N-terminal extracellular leucine-rich in this chapter). HMGB1 is also released prior to hyperexcitable
repeat sequence and an intracellular Toll/IL-1 receptor/resistance states, such as seizures, and modulates glutamatergic signaling.119a
motif (TIR).170 TLR signaling operates through key adapter pro- Neuroimmune activation and neuronal signaling could be inter-
teins that initiate the signaling cascade upon ligand recognition. connected by DAMP release. Several cytokines have been found
All TLRs, except for TLR3, utilize the MyD88 adapter protein to regulate normal brain function and could be dysregulated by
complex. TIRAP/MyD88 complex formation causes activation drugs of abuse. Thus DAMP and cytokine paracrine and autocrine
of the IL-1 receptor–associated kinases (IRAKs) and the TNF signaling across glia through kinase cascades may represent brain
receptor–associated factor 6 (TRAF6) leading to IκB and MAPK plasticity mechanisms that could contribute to the development
activation. IκB and MAPK activation result in activation of the of addiction
nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-κB) and activated protein-1 (AP-1) transcription factors, Immune Signaling Molecules as
respectively. These transcription factors regulate the expression
of proinflammatory cytokines that propagate and magnify the Neuromodulators
immune response. Because TLRs share common intracellular sig- In the brain, the neuroimmune system functions not only to
naling with several cytokines, subsequent cytokine release leads to address foreign pathogens, but also regulates normal brain func-
an amplification of immune responses. Activation of these tran- tion. Recently, numerous immune signaling molecules have also
scription factors is involved in addiction (detailed below). TLR been found to be important for synaptic activity, learning, and
signaling was initially described in peripheral immune cells. Thus memory. For example, the classic proinflammatory cytokine TNFα
the precise signaling pathways for the TLRs in each brain cell type is required for development of long-term potentiation (LTP) in
have yet to be delineated. Both microglia and astrocytes appear to the visual cortex168 and is critical for synaptic strength.18 At higher
show canonical TLR4 signaling in response to ethanol resulting concentrations, however, TNFα disrupts LTP.171 This translates
in NF-κB activation. However, responses in neurons are poorly into behavioral alterations, as TNFα-overexpressing mice show
understood. There is debate on whether neurons are capable of decreased performance on spatial learning and memory tasks.4
Chapter 20 Neuroinflammatory Processes in Drug Addiction 279
Neuroimmune Activation and mediators have been found to play important roles at various
the Cycle of Addiction stages.
TLR antagonists During the binge/intoxication stage, several immune-regulat-
Microglial inhibitors ing interventions have been found to alter alcohol consumption.
Phosphodiesterase E4 inhibitors Immune activation by injection of the TLR4 agonist lipopolysac-
Cycloxygenase inhibitors charide (LPS) increases ethanol consumption in mice,29 whereas
IL-1RA, IL-10 local knockdown of TLR4 in the central amygdala also decreases
ethanol self-administration.114 MCP-1 increases alcohol self-
administration after intracerebroventricular injection in rats.177
MCP-1 Binge HMGB1, TNFα, IL-16 Meanwhile, the antiinflammatory mediators IL-1 receptor antag-
IL-6 Intoxication onist and IL-10 each reduce alcohol self-administration when
injected into the basolateral amygdala.121,122 Blocking IL-1β sig-
Withdrawal
naling in the VTA also prevents cocaine-induced dopamine release
Behavioral and Negative in the nucleus accumbens.130 Furthermore, ablation of certain key
Disinhibition Affect neuroimmune genes, such as IL-6, IL-1ra, Ccr2, Ccl2, and Ccl3,
decreases ethanol consumption.28,30 Compounds that inhibit
microglia also reduce the binge/intoxication stage. Minocycline, a
Craving and microglial inhibitor, reduces ethanol self-administration1 and con-
TNFα Preoccupation DAMPs and
IL-1β Cytokines
ditioned place preference to cocaine.130 An analysis of genetically
IL-8 paired rodents found that high ethanol drinking animals show
IL-6 increased NF-κB and other proinflammatory gene expression.128
IL-1β antagonists
These studies suggest that neuroimmune activation may play a
role in the rewarding properties of drugs of abuse. However, care
• Fig. 20.1 Neuroimmune contributions during the various stages of addic- should be taken when extrapolating rodent studies to humans, as
tion. in addicted humans, the rewarding properties of drugs of abuse
shift from the drug itself to cues associated with the drug.102 The
majority of rodent work to date has been done in nondependent
The cytokine IL-1β also modulates LTP, promoting it at lower lev- animals and should be interpreted in that context.
els, but disrupting LTP at higher concentrations.74,147,148 In addi- Neuroimmune activation also occurs during the craving/pre-
tion, IL-1β modulates neuronal GABA transmission in the central occupation stage. In human alcoholics, increased plasma levels
amygdala.11,12 The M2 (antiinflammatory) microglia-associated of multiple proinflammatory cytokines have been found such as
protein TGF-β1 promotes LTP and object recognition memory.40 TNFα80 (which correlates with severity of alcoholism), and IL-1β,
IL-4 and IL-13 knockout (KO) mice show learning and memory IL-6, and IL-8, which correlate with alcohol craving.80,108 TNFα,
impairments.34,62 The inflammatory chemokines MIP-1α and IL-6, and IL-1β each cross the blood-brain barrier to exert their
CX3CL1 also regulate synaptic plasticity and memory func- CNS effects.16,17 Infusion of the opioid-insensitive TLR4 antago-
tion.22,119 CX3CL1 KO mice show impaired LTP, whereas exog- nist (+)-naltrexone during withdrawal reduces cue-induced hero-
enously added MIP-1α impairs LTP. These immune-associated ine seeking.173 More work needs to be done to discern the role of
molecules have multiple functions. Thus in the brain, immune neuroimmune activation in the craving of drugs of abuse. How-
signaling molecules seem to function as endogenous neuromodu- ever, these findings suggest a potential role and a possibility of
lators. Disruption of the expression or release of these molecules immune therapeutics to prevent drug-associated craving.
by drugs of abuse could alter synaptic activity and behavior. Neuroimmune activation is also involved in the withdrawal/
negative affect stage of addiction. A large body of literature does
suggest that the development of negative affective states such as
Addiction as a Neuroimmune Disease anxiety and dysphoria contribute to the maintenance of addic-
tion.101 The negative affect stage is often described as stress. It
Neuroimmune Components of the Stages of is thought that continued substance abuse is an attempt to alle-
Addiction viate these negative states. Alcohol withdrawal causes increased
inflammatory cytokines in the brain.101 In addition, intracerebro-
The neuroimmune contribution to the pathology of addiction has ventricular injection of cytokines sensitizes anxiety-like behavior
become the topic of recent numerous reviews.b Neuroimmune during alcohol withdrawal.33 Thus, cytokine induction is thought
signaling has been identified in each of the stages of addiction. The to contribute to negative affect associated with withdrawal.
pathology of addiction has been modeled by a three-stage process Heightened activation of stress pathways during withdrawal also
to identify different features that may be targeted by interven- cause neuroinflammation. Stress causes sensitization of microg-
tion.58,183 Addicted individuals cycle through binge intoxication, lia to inflammation in an HMGB1-dependent manner.191 TLR4
withdrawal and negative affect, craving, and preoccupation, and activation modulates serotonin transporter (SERT) function and
back to binge intoxication102 (Fig. 20.1). Much work remains to increases depression-like behavior.199 Furthermore, various types
be done to better understand the impact of innate immune acti- of acute and chronic stress causes microglia activation in mul-
vation during the various stages; however, several inflammatory tiple brain regions175 and leads to depression-like behavior. The
proinflammatory cytokines TNFα, IL-6, and IL-1β contribute
to the pathologies of mood disorders.20a,20b Agents that inhibit
bReferences 15, 49, 51, 52, 54, 56, 57, 86, 115, 123, 124, 126, 129, 156, microglial activation block the development of depression-like
180. behavior.69,103,175,194 Ethanol increases microglial markers such
as CD11b and Iba1,66,149 consistent with microglial activation, responses to ethanol. This leads to NF-κB activation and ampli-
and primes the microglial response to peripheral inflammation.149 fication of immune responses. Ethanol causes NFκB activation
In addition, stress also causes NF-κB activation. Human psy- in neurons in brain slice culture45,200 and in vivo.189 Although
chosocial stress causes NF-κB activation in blood monocytes.23 the unique cellular activation patterns need to be further eluci-
Restraint stress in rodents causes NF-κB activation with subse- dated, it is clear that ethanol activates NFκB in brain. Ethanol
quent production of TNFα and proinflammatory prostaglan- increases NFκB-DNA binding both in vivo in mice47 and in vitro
dins.23,117 Ethanol activates NF-κB in rat and mouse brain,151,189 in rat hippocampal-entorhinal cortex slice culture.200 Ethanol
and human astrocytes.60 Therefore, it is clear that both stress and also induces NFκB target genes, such as MCP-1,79 proinflam-
alcohol can affect glia and lead to neuroimmune activation. The matory cytokines (TNFα, IL-1β, and IL-6),152 proinflamma-
exact neuroimmune milieu associated with drug withdrawal– tory oxidases (iNOS,3,201 COX,3,25 and NOX155), and proteases
induced stress is not clear. However, stress pathways overlap with (TNFα-converting enzyme [TACE] and tissue plasminogen acti-
neuroimmune pathways associated with drug withdrawal and are vator [tPA]).201 Cocaine also causes NF-κB activation in vivo that
clearly activated. Further work needs to be done to determine the is required for increased conditioned place preference.5,161 The
exact contributions of neuroimmune activation to negative affect exact mechanism of TLR activation by alcohol and other drugs
and stress associated with drug withdrawal. of abuse is not clear. However, the involvement of multiple TLRs
as well as the coordinate induction of endogenous TLR-activating
DAMPs suggests a DAMP-mediated phenomenon.
Neuroimmune Signaling in Alcoholism
Alcohol use activates the neuroimmune system, contributing to The Role of Endogenous TLR Agonist DAMPs in
the development of alcohol use disorders.49,52,56,180 Findings from
postmortem human alcoholic brain tissue, rodent studies, and cell the Pathology of Addiction
culture work support this hypothesis. Postmortem human alcoholic The key role of TLR signaling in the neuroimmune pathology of
brains show increased microglial79,160 and astrocyte markers.160 addiction begs the question of—What is the mechanism of TLR
Postmortem human alcoholic brains show increased expression of activation? The brain is typically a sterile environment; how-
neuroimmune molecules, such as MCP-1, TLR2, TLR3, TLR4, ever, TLRs are expressed and follow differential developmental
TLR7, and HMGB1.50,79 Ethanol exposure studies in vivo also expression patterns.95 Certain TLRs have also been found to
find increased expression of TLRs2–4 in cortex and cerebellum, have nonimmune functions, such as TLR3 and TLR8, which
with subsequent NF-κB activation and cytokine induction.50,113 regulate axonal and neurite outgrowth, respectively.39,116 Thus
Binge alcohol treatment persistently increases neuroimmune mol- TLR signaling occurs in brain function in the absence of infec-
ecules such as TLR3, TLR4, HMGB1, and RAGE. 179,181 Etha- tion, through the release of endogenous TLR agonists. This led
nol also sensitizes neuroimmune responses to TLR3 and TLR4 to the hypothesis that TLR activation in addiction is mediated
agonists.149,154 Studies in vitro find that ethanol directly activates through the release of endogenous agonists. Indeed, induction
immune cells. Alcohol activates microglia in vitro, increasing of DAMPs has been found in the pathology of alcoholism. The
expression of TNFα, IL-1β, iNOS, and NADPH oxidase.66,149,155 endogenous TLR4 and RAGE agonist, HMGB1, in particu-
In addition, alcohol activates astrocytes, with increases in lar, has been identified as a critical neuroimmune mediator in
GFAP.3,71 These effects in vitro and in vivo involve TLR activa- alcoholism. HMGB1 is increased in postmortem human alco-
tion. TLR4 activation has been shown to play a pivotal role in holic brain in several brain regions and correlates with lifetime
alcohol-induced neuroimmune signaling.3 TLR4 KOs and TLR4 alcohol consumption.45,50,179 Ethanol administration in vivo
KO glia are protected from much of neuroimmune activation by increases HMGB1 in cortex and cerebellum.50,113 In addition,
ethanol including glial cell activation, NF-κB activation, caspase-3 microglia secrete HMGB1 in response to ethanol as well as
activation, anxiety-like behavior, and memory impairment.c tobacco smoke extract.42,45,50,106,203 Thus ethanol and other
Astrocytes treated in vitro with siRNA against TLR4 or MD-2 drugs of abuse can cause sterile inflammation by the release
and CD14 (critical adaptor molecules for TLR4 signaling) are of HMGB1. Recently, ethanol has been found to cause TLR7
protected from ethanol-induced NF-κB induction.25 In addition, activation through the vesicular secretion of the miRNA let-7b
ethanol increases the formation of TLR4/TLR2 heterodimers in DAMP.45 Let-7b binds the single-stranded RNA sensing TLR7
microglia cell membrane, causing iNOS induction and MAPK leading to neuroimmune activation and neurodegeneration.
activation.65 Both TLR4 and TLR2 KOs were protected. In an HMGB1 is actually required for immune responses to TLRs
alcohol-preferring rat strain (p-rats), increased expression of TLR4 3, 7, and 9.196 Therefore, HMGB1 may represent a critical
in the VTA was found to correspond with binge ethanol respond- modulator of multiple neuroimmune signals. Indeed, blocking
ing,92 with TLR4 expression being regulated by GABA(A)α2 HMGB1 release prevents cytokine induction by chronic etha-
receptor114 and the stress-associated corticotropin-releasing fac- nol.193 Methamphetamine also induces HMGB1 in vivo and
tor (CRF).92 TLR4 activation has also been implicated in cocaine in vitro, with HMGB1 inhibition preventing neuroimmune
and heroin abuse.130,143,173 Furthermore, ethanol-induced innate activation by methamphetamine.70
immune activation caused impairment of short and long-term
memory for object recognition in mice.137 This was accompanied Neuroimmune Activation and the Progression to
by a reduction of H3 and H4 histone acetylation as well as histone
acetyltransferase activity in the frontal cortex, striatum, and hippo- Addiction
campus. TLR4 KO mice were protected from behavioral impair- The progression from drug or alcohol abuse to addiction occurs
ments and histone modifications. TLR7 has also been identified over time (Fig. 20.2). This progression often begins during ado-
as important in neuroimmune activation by ethanol leading to lescence. Alcohol and drug abuse during adolescence are com-
hippocampal neurodegeneration, and should be investigated fur- mon.107 Regarding alcoholism, the age at drinking onset is
ther.45 Activation of TLRs is a central feature in the neuroimmune strongly related to the risk of developing an alcohol use disorder
Mutiple Bings Over Lifespan Promote paracrine signaling.144,151,172 Each progressive binge may increase
Neuroimmune and Behavioral Pathology the neuroimmune baseline, leading to further damage and pathol-
ogy. This “smoldering” level of inflammation due to repeated drug
Persistent Neuroimmune binges, as is typical with alcoholism and drug abuse, might under-
Neuroimmune Dysfunction pin the transition from abuse to addiction. Intervention of this
Activation
feature of disease pathology might belay this transition.
DAMPs (e.g., HMGB1) Another important cognitive feature in the progression to
Withdrawal-Stress addiction is a loss in frontal cortical mediated executive function.
These functions include motivation, planning and goal setting,
and behavioral flexibility. Frontal cortical dysfunction results in
Abuse Intoxication Withdrawal Addiction perseveration and repetition of previously learned behaviors due to
failure to associate new information (e.g., negative consequences)
into decision-making. Binge drinkers report more negative
Craving mood and perform worse on executive functioning tasks.174,192
Executive function In alcoholics this is common48 and manifests in impulsivity and
behavioral inflexibility. Reversal learning—the ability to change
Cognitive previously learned behaviors—is an index of behavioral flex-
Function ibility.162,165 Both human alcoholics68,91 and cocaine addicts165
Persistent Cognitive
Dysfunction
demonstrate reversal learning deficits. Rodents also show persis-
tent deficits in reversal learning following binge ethanol9,43,132 or
Adolescence Adulthood
cocaine.38,163 Frontal cortical function is key in this circuitry that
involves loops between the prefrontal cortex, striatum, and amyg-
• Fig. 20.2 Multidrug exposures amplify neuroimmune signals and cogni- dala.84 Frontal cortical regulation of mood and cognition occurs
tive decline. through reciprocal glutamatergic connections with multiple brain
regions. A hyperglutamatergic state has also been demonstrated in
both cocaine- and stimulant-addicted brains.157 Astrocytes are key
in adulthood.61,75 Adolescence is a unique developmental period regulators of synaptic glutamate levels. Ethanol exposure induces
during which maturation of key structures that regulate cogni- NF-κB activation in astrocytes, leading to increased expression
tive function and decision-making occurs (for review see Crews of proinflammatory genes140,200,201 and impaired astrocyte gluta-
et al.54). Binge drinking during this time has long-lasting effects mate transport.202 Increased extracellular glutamate levels cause
including persistent neuroimmune activation, leading to pro- enhanced neuronal excitation, microglial activation, and excito-
longed cognitive dysfunction.43,179 Indeed, neuroimmune mark- toxicity.190,200 TLR4 KOs are protected from this ethanol induced-
ers in alcoholics correlate with lifetime alcohol consumption hyperglutamatergic state and its associated neurotoxicity.3,100
and age at drinking onset,45,50,52,179,181 with some remaining Innate immune gene induction in the frontal cortex contributes to
elevated long after ethanol administration, during abstinent peri- glutamatergic hyperexcitability and the impairment of executive
ods.45,50,179 It is well known that repeated cycles of binge exposure function.100,156 Thus, neuroimmune activation by ethanol may be
and withdrawal amplify alcohol-induced pathology.32,120 This is a component of the progressive development of hyperexcitability
similar to the innate imune system, as autocrine and paracrine and cognitive dysfunction seen in alcohol use disorders.
signaling by the release of DAMPS, such as HMGB1, amplify
immune responses with each recurring exposure. This amplifica- Neuroimmune Basis of Addiction—A Work in
tion might be similar to an LTP-type of phenomenon, and could
represent neuroimmune plasticity. This is interesting, especially Progress
given the modulation of LTP systems in the brain by many proin- We have presented much of the work that shows that neuroim-
flammatory cytokines. The recurrent and persistent NF-κB activa- mune activation is a key feature in the pathology of addiction.
tion by repeated alcohol or drug intake might mimic a chronic However, much work remains to be done. Little research has
inflammatory state. This is supported by the increased innate been done regarding brain regional differences in neuroimmune
immune markers in the postmortem brains of human alcohol- responses to drugs of abuse. Each brain region has specific popula-
ics,45,50 as well as the upregulation of NF-κB target genes.135 This tions of neurons that may respond differently to alcohol and other
persistent and chronic immune response has also been seen after drugs of abuse. Furthermore, the complex interactions between
one dose of systemic LPS, a TLR4 agonist. One administration of cell types—neurons, microglia, and astrocytes—need to be fur-
high-dose LPS (5 mg/kg) causes persistent microglial activation ther elucidated. In Fig. 20.3, we summarize some of the cell-cell
with ongoing ROS generation leading to dopaminergic neuron interactions between neurons and glia regarding HMGB1, let-7b,
loss over a period of months.152 Although seemingly on a lower and TLRs 4 and 7. However, there remains much to be discovered
scale, binge-ethanol causes similar pathophysiology.13,154,201 The regarding these interactions. In addition, the interaction between
recurrent and prolonged amplification of neuroimmune responses stress, psychiatric disorders, and drugs of abuse on the neuroim-
causes TLR and NF-κB activation, leading to further increased mune system is also likely very important in human populations.
TLR expression, cytokine production, and DAMP release. This Stress is a key feature in the cycle of addiction; however, addiction-
involves the release of HMGB1 as well as miRNA-let-7b -con- related stress needs to be better differentiated from other non–
taining microvesicles.14,45,169 Let-7 isoforms are increased in post- addiction-related stressors. A hypothesis is presented in this chapter
mortem human alcoholic brain and in rodent chronic ethanol of stress and drug-induced neuroimmune signaling that inactivates
models.111,131 Furthermore, ethanol induces ROS generation that frontal cortex and sensitizes limbic circuitry. This leads to persis-
also activates NF-κB and leads to further cytokine release and tent increases in TLRs and DAMPs (e.g., HMGB1) amplified by
Glial-Neuronal Neuroimmune Signals in Alcohol Addiction
HMGB1
IL1β TNFα
Astrocytes
Μicroglia
TLR4
B1
G
HM
GLUTAMATE
TLR4 ATP
TLR4 HMGB1
TLR7
TLR7
HMGB1 Alcohol
(ethanol) Neurons
HMGB1/miRNA let-7b
• Fig. 20.3 Neuron-glia cell-cell interactions in neuroimmune responses to alcohol.
cycles of stress and intoxication. Innate immune signaling impacts alter synaptic signaling.104 For example, IL-1β reduces eIPSCs
cognitive and emotive function, leading to dysfunction.59,77,134,197 in the central amygdala to modulate ethanol effects on GABA
These mechanisms might underlie the progressive and persistent receptors.11 Therefore, significant exploration of immune thera-
nature of addiction. Currently, neuroimmune mechanisms have pies in various models of alcohol abuse is warranted. Many US
been most studied in the context of alcohol abuse and alcoholism. Food and Drug Administration (FDA)–approved drugs have also
Considerable emerging evidence supports a role for HMGB1/ been found to have antiinflammatory actions in the CNS. Table
TLR signaling, innate immune gene induction, and alterations in 20.2 lists some candidate drugs that have been found to be ben-
epigenetics and neurotransmission as culminating in the neurobi- eficial in the context of addiction or other neuroimmune condi-
ology of alcoholism. 54,58,180 Innate immune activation and TLR tions. For example, minocycline is a tetracycline antibiotic and
signaling seem to be essential for ethanol induction of pathology. microglial inhibitor146 that prevents ethanol induced–microglial
Ethanol and other drugs of abuse promote innate immune gene activation and reduces alcohol self-administration.1,149 A recent
induction.52,79,155 which seems to be linked to changes in execu- human study found that in a laboratory setting minocyline did
tive function, reinforcement-reward, and negative affect-craving- not alter subjective responses to ethanol or ethanol-induced
anxiety to promote addiction.180 Although much of this work is craving; however, alcohol self-administration has not yet been
convincing regarding the presence of a role of neuroimmune acti- reported in humans.143a Phosphodiesterase 4 (PDE4) inhibitors
vation involvement in the pathology of addiction, there remain reduce inflammation by increasing cAMP concentration, resulting
many gaps regarding the precise mechanism and the significance in reduced NF-κB activation.90 Recently, these agents have been
of immune activation. Nonetheless, significant findings exist to found to reduce ethanol intake in rodents.19,27,81 A recent phase 2
warrant the investigation of neuroimmune therapies for efficacy clinical trial using the PDE4 inhibitor ibudilast showed beneficial
in the treatment or prevention of addiction. effects, including improvements in mood after stress and alcohol-
cue exposures, and reduced levels of tonic craving.155a A different
placebo-controlled trial found that ibudilast reduced some of the
Future Immune Therapies for Addiction rewarding effects of methamphetamine.195 PPARγ agonists might
also be helpful in alcohol use disorders through their antiinflam-
Toward Novel Addiction Treatment Strategies matory activities. The PPARγ agonist pioglitazone is a microglial
Based on Immune Pharmacology inhibitor166 that reduces neurotoxicity in fetal alcohol spectrum
disorder models63,94 that could potentially play a beneficial role
Given the data presented, several potential neuroimmune thera- in alcoholism. Each of these drugs, and others with antiinflamma-
pies are given in Table 20.2. Some of these medications are cur- tory actions, should be investigated for their potential efficacy in
rently being tested in clinical trials for alcohol use disorders. Due alcohol use disorders.
to the challenges to the human condition associated with translat-
ing animal models of alcohol and drug abuse, and gaps in knowl- Acknowledgments
edge, it is unclear whether these therapies would be of highest
benefit for prevention or recovery from addiction. It is known that We thank the National Institute on Alcohol Abuse and Alcoholism
neuroimmune activation and addiction can cause neurodegenera- for its support through the Neurobiology of Adolescent Drinking
tion.51,152,158,184,186 Although immune therapies would likely not in Adulthood (NADIA) consortium (AA020024, AA020023),
be of benefit in brain regions where neurodegeneration has already the Bowles Center for Alcohol Studies (AA011605), and the U54
occurred, there may still be a benefit for recovery of normal syn- collaborative partnership among NCCU, and UNC (AA019767),
aptic function and neuroplasticity. Microglia and cytokines can and K08-AA024829.
TABLE 20.2 P
otential Neuroimmune Therapies for the Treatment of Addiction
Drug Mechanism Primary Immune CNS Activity
Minocycline Tetracycline antibiotic Reduces alcohol self-administration1
Microglial inhibitor Reduces ethanol microglia activation149
Prevents reinstatement of morphine and amphetamine seeking6,7
Rapamycin Macrolide antibiotic mTORC1 inhibitor Reduces binge ethanol intake in male patients46
Neuroprotection via autophagy promotion41,145
Azithromycin Macrolide antibiotic Promotes antiinflammatory M2 microglial activation state198
Microglial inhibitor
Rifampin Bacterial RNA polymerase inhibitor Inhibits microglia activation to TLR421,187
TLR4 inhibition
Indomethacin COX-2 inhibitor Reduces alcohol self-administration73
Reduces ethanol neurotoxicity140
Simvastatin HMG-CoA Reductase inhibitor Reduces inflammation and neurotoxicity to ischemia and injury112,164
NF-κB inhibition
Glycyrrhizin HMGB1 inhibition Blocks ethanol-induced cytokine release203
Reduces neuroinflammation after traumatic brain injury133
Pioglitazone, DHA PPARγ agonists Reduce toxicity and proinflammatory cytokines in fetal alcohol spectrum
disorder model63,94
Ibudilast, mesopram, Phosphodiesterase 4 inhibition Reduce ethanol intake in C57BL/6J mice27
rolipram, CDP 840 Reduces ethanol self-administration in rats19
Naltrexone/naloxone μ-Opioid antagonists Reduces alcohol self-administration
and nalmefene TLR4 inhibition Binds TLR4 adaptor protein MD282,188
Prevent neuroimmune activation by ethanol125
Etanercept TNFα antagonist Prevents REM sleep disruption in alcoholics83
CNS, Central nervous system; HMGB1. high-mobility group box; NF-κB, nuclear factor kappa B; REM, rapid eye movement; TLR, Toll-like receptor; TNF, tumor necrosis factor.

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Neuroinflammatory Processes in Drug

HMGB1. High-mobility group box.

Glial-Neuronal Neuroimmune Signals in Alcohol Addiction

• Fig. 20.3 Neuron-glia cell-cell interactions in neuroimmune responses to alcohol.

References behavior in rat. Prog Neuro-Psychopharm Bio Psychiatry. 2014;53:

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